How Do Pain Medications Work In Pets?

If you are a current pet owner or have been in the past, there is a 99% chance your pet has had pain medication at some point in their life.  Or they have at least had it prescribed or suggested for them.

For us to fully weigh up what we are administering to our pets, it makes sense to start with the basics.

So, how do pain medications work in pets?

Pain medications come in different forms, but there are a few common ones:
  • NSAIDs
  • Opioids
  • Paracetamol


Non-steroidal anti-inflammatory drugs are exactly what they say on the tin – they are used to reduce inflammation.

Inflammation is an immune response.  When something becomes damaged or threatened in the body, compounds are released which kick start an immune response to help fight the threat or heal the trauma.

A Guide to Inflammation in Pets

NSAIDs are typically divided into groups based on their chemical structure and selectivity.  They include:

acetylated salicylates (aspirin)
non-acetylated salicylates
propionic acids (ibuprofen)
acetic acids (diclofenac)
enolic acids (meloxicam)
anthranilic acids (meclofenamate)
naphthylalanine (nabumetone)
selective COX-2 inhibitors (celecoxib)

The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX).

Cyclooxygenase is required to convert arachidonic acid (a polyunsaturated omega-6 fatty acid) into thromboxanes, prostaglandins, and prostacyclins (which are all inflammatory mediators).  The therapeutic effects of NSAIDs are therefore attributed to the reduction of them.

Many NSAIDs are not selective, meaning they take out all COX enzymes; this is beneficial if we are targeting inflammatory mediators, but COX enzymes also carry out other roles in the body.

COX1 enzymes play a role in:

protecting the gastrointestinal tract
renal blood flow
platelet aggregation

This is why proton pump inhibitors are often administered alongside NSAIDs, the reduction in stomach acid secretion is thought to reduce the risk of gastrointestinal side effects.

In addition, there is also evidence of long term NSAID use and chronic kidney disease.

The administration of certain NSAIDs can also trigger hypersensitivity reactions. Non-selective NSAIDs exert effects by inhibiting COX-1 and subsequently shift arachidonic acid metabolism from prostaglandin (especially PGE2) synthesis toward pro-inflammatory cysteinyl leukotrienes (LTs) such as LTC4, LTD4, and LTE4.  Overproduction of LTs leads to activation of mast cells and eosinophils, which can result in typical allergic symptoms like itching and hives, along with bronchoconstriction.

This is worth noting if you have a particularly sensitive dog.


Opioids function primarily in the nervous system; they inhibit neurotransmitter release.

The Neuroscience of Pain

Morphine is commonly considered to be the archetypal opioid analgesic and the agent to which all other painkillers are compared.

There is evidence to suggest that as long ago as 3000 bc the opium poppy, Papaver somniferum, was cultivated for its active ingredients.

But, it wasn’t until morphine was isolated from opium in 1806 by Sertürner that modern opioid pharmacology was truly born.

In 1847 the chemical formula for morphine was established and this, coupled with the invention of the hypodermic needle in 1853, led to the widespread clinical use of morphine.

How Does It Work?

Opioid receptors are distributed throughout the central nervous system and within peripheral tissue of neural and non-neural origin.  Opioids reduce excitability of neurons, and decrease the release of nociceptive neurotransmitters like substance P.  See our blog on The Neuroscience of Pain above to learn more about this.

Because opioids work in the nervous system, in essence slowing everything down, the concern is that they may do it a little too well and knock everything a little out of whack.  As we know the body likes balance, and it does everything in its power to keep it that way.

To this end, behavioural side effects of opioids include panting, vocalisation, salivation, nausea, vomiting, defecation, and sedation or hyperactivity.

Physiological side effects of opioids in dogs may include central nervous system depression, respiratory depression, bradycardia, usually accompanied with little to no change in cardiac output, ileus, and urinary retention.

Findings Here


It has been assumed that paracetamol probably acts through the cyclooxygenase (COX) pathway.  This is the pathway through which the nonsteroidal anti-inflammatory drugs (NSAIDs) act.

Much investigation has focussed on paracetamol’s inhibition of the COX enzyme because its analgesic and antipyretic effects are similar to those of aspirin, the archetype NSAID.

However, paracetamol does not have significant anti-inflammatory activity, or does it inhibit production of the pro-clotting TXAs. In addition, paracetamol does not appear to have a major effect peripherally; its action appears to be mostly central. It seems reasonable to assume that although there may be some effect on COX enzymes, this effect is different from that seen with typical NSAIDs.

Because of this, other mechanisms of action have been considered.

It is thought that serotonin has a major role in modulating pain perception. Serotonergic drugs are used in the treatment of migraine headaches in humans and combined serotonin-norepinephrine reuptake inhibitors have been used in chronic pain management.  It has been considered that paracetamol, in effect, activates serotonin pathways to influence pain perception.

Other data has indicated that when cannabinoid receptors are blocked, paracetamol loses its action, suggesting the endocannabinoid system may play a role in paracetamol’s actions too.

Findings Here

Whilst we may not know the full mechanism of action of paracetamol, it is possibly the widest used pain medication

The side effects usually associated with paracetamol include:

yellowing of white of eyes or gums (jaundice)
reduction in appetite
vomiting or diarrhoea
blood in faeces

Are There Any Other Pain Medications Worth Mentioning?

There are a number of products on the market which target pain, but they could fill a book, so we’ll just take a look at two more.


Librela is an injectable which targets pain in cases of osteoarthritis.

The active ingredient in librela is bedinvetmab which is a monoclonal antibody.  This antibody (or protein) is trained to recognise and attach to a protein known as Nerve Growth Factor (NGF).

Once attached it prevents NGF from attaching to its own receptors on nerve cells and therefore is thought to stop the transmission of the pain sensation.

What Is Nerve Growth Factor?

Nerve growth factor (NGF) is one of a group of small protein-like molecules called neurotrophins.  Researchers consider that NGF may promote the growth, maintenance, and survival of neurons and axons. It’s also thought to help repair the myelin sheath, which is the insulating coating around the axons which helps send messages around the nervous system, quickly and efficiently.  Animal experiments have found that as the production of NGF decreases in the brain, the animals’ ability to form new connections and to retain and access memories becomes impaired. They believe NGF might save degenerating nerves and help restore their function.  Researchers have explored the role of NGF throughout development and have found that NGF null mice have a severe loss of sympathetic and sensory neurons.

The product sheet outlining their 6-month laboratory study and 3-month field study can be found here:

Librela Product Sheet

Many dogs are presenting with increased thirst, increased urination and incontinence coincidentally with this the administration of this product.


If you have read any of our blogs on nervous system function, you may remember the neurotransmitter GABA.  This is the brakes of the system, it helps reign everything back in.

Gabapentin was designed to mimic GABA as an anti-convulsant medication, it short, it was designed to treat epilepsy in humans by reducing excitation in the nervous system.

But it turns out it doesn’t act on GABA receptors at all.

It seems to block calcium channels, preventing calcium influx.  Therefore, it reduces the release of glutamate (an excitatory neurotransmitter) along with substance P (a neurotransmitter involved in pain perception).

Its use in pets in off-label.

It is thought that gabapentin is largely unprocessed by the liver and so reaches the kidneys unchanged.  In human data, it has been concluded that gabapentin toxicity in patients with chronic kidney disease is under-recognized. Patients with chronic kidney disease often receive inappropriately high gabapentin dosage for their kidney function, occasioning overt toxicity.  This is even more of a concern in the ageing patient.

As science and medicine progress, there will be additional medications that reach the market.  If we are to make informed decisions around the care of our pets, we need access to information.

We hope this has provided some insight into how some pain medications work.

Thanks for reading,

MPN Team ‍

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